Of mice and mending

Professor Phil Hansbro is unconventional but effective, employing a number of experimental mouse models to investigate – and manipulate – the hallmark features of respiratory disease.

Hansbro's plan of attack on the diseases of our airways is quite simple – understand their pathogenesis to identify new avenues of therapy. Equal parts scientific and artistic, the ambitious academic's two-pronged approach is recognised internationally
as a valuable, ongoing contribution to the field, affording researchers the opportunity to dissect and study the intricate architecture of multiple chronic inflammation disorders.

'Examining their development in humans is expensive and labour intensive,' he concedes.

'People can smoke for 10, 25, 50 years before they get emphysema.'

'Inducing them in laboratory mice, which are inbred and so identical, means that our work is well controlled.'

'We can be specific about the things we test for and find.'

The integration of molecular biology theory and practice, these novel models allow Hansbro and his team to explore respiratory disease and infection from several cellular angles. With expertise and particular emphasis on immunity, physiology and lung function analysis, their simulations of key pathogenic
events excite those both in and out of the laboratory.

'Our research outcomes have a translational goal,' Hansbro explains.

'We aim to show that what we discover is important for human diseases too.'

Similarly acknowledging the importance of sticking to a realistic timeframe, the Hunter Medical Research Institute innovator employs both short-term and long-term studies.

'We're focused on identifying potential treatments for severe asthma and chronic obstructive pulmonary disease (COPD), also known as emphysema,' he declares.

'Existing treatments only partially suppress exacerbations and some don't work at all.'

'Sufferers are more susceptible to respiratory infections too, so we need to work out why this is and find ways to manage them – or better yet – prevent this co-morbidity altogether.'

Dynamic networks

Taking a 'very roundabout route' to get to this point, Hansbro began his research career in organic chemistry. The English native completed a PhD in the discipline at the University of Leeds in the early 90s, principally using it to investigate intracellular signalling pathways relevant to cancer.

'This involved isolating enzymes and using them to make compounds to produce biomembranes that release molecules, which when over-produced, are important in cancer,' he instructs.

The energetic scholar then headed across the ocean to Australia to undertake post-doctoral studies into protein biochemistry. Also involving elements of microbiology and molecular biology, this endeavour inspired a widening of research fields and goals.

'This allowed us to explore the functions of these and other enzymes and molecules involved in muscle disease and respiration in some depth,' he states.

After these studies he moved back to England, taking up residency at the University of Cambridge in 1997 to design and test new vaccines against infection with the bacteria Streptococcus
pneumoniae. The three-year appointment proved to be a mix of new and old for Hansbro, piquing his scientific curiosity in airway inflammation while also enabling him to continue using a range of microbiological and molecular techniques.

'Streptococcus pneumoniae is a major respiratory pathogen,' he reveals.

'It is the commonest cause of pneumonia and is also an important inducer of meningitis, blood and ear infections.'

Hansbro continued exploring the pathogenic bacterium after being recruited to the University of Newcastle, Australia, in the late 90s, impressively identifying a number of factors that protect against asthma. Developing them into therapeutic strategies for the last 15 years, the research leader is
set to go into clinical trials with them 'some time' in 2015.

Gut reaction

In a simultaneous attempt to produce novel treatments for other respiratory diseases, Hansbro is conducting an extensive series of studies of the lower respiratory tract. The immunologist is investigating the role of inflammatory features and immune cells involved in the disease and is hoping his studies
will help firm up understanding of the pathogenesis of COPD.

'In some experiments we're trying to determine the bacterial changes that occur in the lung and gut during the development of COPD,' he clarifies.

'So far we've found that smoking can alter the bacteria that make up the microbiome in the gut.'

'It also might be possible to 'drown out' emphysema-related bacteria using faecal transplants.'

Comically labelled 'transpoosion,' the unsavoury science involves taking faeces from healthy mice and putting them in the guts of those with COPD. No laughing matter though, this 'repoopulation' remedy may treat the symptoms of the disorder and/or protect against its development.

'We're in the process of studying bacteria that may be involved and discovering exactly what they do and what they are,' Hansbro divulges.

'The idea is that we'll eventually be able to develop new antibiotics or other therapies against them.'

Damage control

A master of many disciplines, Hansbro is concurrently running an experimental trial of epigenetic inhibitors. Acknowledging the increased production of inflammatory genes when people are overexposed to smoke and air pollution, the esteemed educator and investigator is looking to find ways to prevent
harmful DNA modifications from occurring.

'Nicotine-induced acetylation causes DNA to unravel, which means it opens up more and allows enzymes to generate greater amounts of these genes,' he explains.

'We're looking at ways of stopping this in mice.'

'Then we can try to work out precisely how the inhibitors suppress disease.'

Exploring the possibilities of therapeutic gene silencing inherent in another form of epigenetics, Hansbro is also in the middle of specifying the function of microRNAs. Once thought to be junk byproducts of RNA, these small pieces are now widely thought to serve as on/off switches for inflammation.

'Some of them potentially target and destroy anti-inflammatory factors,' he claims.

'Knowing exactly how and why they're implicated in respiratory disease will help us to develop effective inhibitors.'

With oxidative stress from smoking similarly linked to pro-inflammatory environments, Hansbro is undertaking a research project on cellular respiration as well.

'We need to work out how mitochondria become altered to produce it,' he asserts.

'Then we can develop inhibitors.'

Two diseases, one knockout blow

Other new therapeutic targets for COPD are being imagined using a system of elimination, with Hansbro and his team 'knocking out' a number of genes in mast cells to infer probable function and identify novel roles. Observing physiological variances between wild mice and the mice that are deficient
in particular factors, their current research implicates mast cells as pathological mediators of several inflammatory conditions.

'Our recent studies show knocking out two different genes causes the mice to get less COPD,' he affirms.

'This tells us how important they are in the disorder.'

Hansbro is also using the mice to explore and understand the pathogenesis of lung cancer. One-upping previous experimental models of the disease, which induce lung cancer in tissues in 9 months, the expert has got it down to just sixteen weeks.

'But we're hoping to cut that time in half,' he shares.

'We can find good treatments for lung cancer if we're aware of how it develops.'

The next phase

Set to translate this research into practice, Hansbro is looking forward to applying his therapies to humans.

'Proving their effectiveness takes a long time,' he admits.

'Once we're sure, we can start exposing our own respiratory cells to allergens or cigarette smoke and using the treatments to suppress elevated inflammatory responses.'

The Associate Director of the University's Priority Research Centre for Asthma and Respiratory Disease is similarly looking forward to celebrating the achievements of his young collaborators at the Hunter Medical Research Institute.

'We really believe in our students and early career researchers,' he avows.

Career Summary

Biography

Professor Phil Hansbro is an internationally recognised research leader in the study of respiratory diseases, such as asthma, chronic obstructive airway disease (COPD, aka emphysema) and infections and is developing interests in lung cancer. His work is substantially contributing to understanding the pathogenesis and developing new therapies for these diseases. Indeed his work has made internationally important contributions and led to the identification of novel avenues for therapy that are under further study. This is achieved through the development of novel mouse models that recapitulate the hallmark features of human disease, including infections, asthma and COPD and now lung cancer. He employs these models in integrated approaches (infection, immunity & physiology with particular expertise in lung function analysis) to understand human diseases, and develop new treatment strategies. Research outcomes have a translational goal and his studies are conducted in parallel with collaborative human studies with clinical researchers. Major achievements:

1. Identified that the age, timing and nature of infection is critical in determining effects on asthma.

2. Determined that Chlamydia infection induces severe asthma in early life and adults.

9. Discovered that a new interferon, IFNε, protects against Chlamydia reproductive tract infection.

10. Developed a novel model of lung cancer that is induced by cigarette smoke.

11. He is also an expert in the study of avian influenza viruses (AIVs) in wild birds and to date his group has collected over 240,000 samples and identified ~250 AIVs.

His group has been recognized by the award of numerous nationally competitive grants, particularly from the NHMRC. Since 2004 he has published ~100 peer reviewed journal articles, with an average impact factor of 5+. These include publications in the leading general (Science [IF=31], Nature Immunology [IF=26]), respiratory (Am J Respir Crit Care Med [IF=12]), allergy (J Allergy Clin Immunol [IF=11]), infection (PLoS Pathog [IF=9]) and immunology journals (J Immunol [IF=6]). He is frequently invited to write reviews in prestigious journals (Pharmacol Ther [IF=8.0], Am J Respir Cell Mol Biol [IF=4.5], Immunology [IF=3.4]), which make substantial contributions to the fields. He is a regular reviewer for national granting bodies and leading international journals.

Prof Hansbro has a high level record of achievement & performance as a research leader recognised by high level appointments (Deputy director of the Centre for Asthma & Respiratory Disease (CARD) & the CRC for Asthma & Airways [CRCAA, UoN 2005-12], Head, Discipline of Immunology & Microbiology [2007-11], joint leader of Infection & Immunity Research Cluster, Director of School Research Committee). These Centres & Groups are internationally recognised for contributions to respiratory & infectious diseases. With Profs P. Foster & P. Gibson has built an internationally recognised, world leading research program with a reputation for excellence in respiratory research; CARD, with state-of-the-art facilities for the study of infection, immunity, histology, respiratory physiology & function.

Research ExpertiseExpertise in the inevstigation of the relationship between bacterial and viral infections and obstructive airway diseases such as asthma and COPD. Expertise in the collection and analysis of avian influenza viruses from wild birds.

Administrative ExpertiseExtensive expertise and experience in University administration and governance. head of Discipline of Immunology & Microbiology, Deputy Head of School of bIomedical Sciences Research Committee and various teaching administration bodies.

Qualifications

PhD, University of Leeds - UK

Bachelor of Science (Honours), Hallamshire University

Keywords

Allergy

Asthma

Avian influenza

Bacteriology

COPD

Epigenetics

Immunology

Infectious diseases

Inflammasome

Inflammation

Lung cancer

Microbiology

Microbiome

Reproductive tract diseases

Respiratory diseases

Virology

Fields of Research

Code

Description

Percentage

110299

Cardiorespiratory Medicine and Haematology not elsewhere classified

25

110799

Immunology not elsewhere classified

75

Professional Experience

UON Appointment

Title

Organisation / Department

Professor

University of NewcastleSchool of Biomedical Sciences and PharmacyAustralia

Academic appointment

Dates

Title

Organisation / Department

Head - Discipline of Immunology & Microbiology

University of NewcastleAustralia

Co-director Infection and Immunity Research Cluster

University of NewcastleSchool of Biomedical SciencesAustralia

Deputy Program Leader - Priority Research Centre for Asthma and Airways, UNEW

University of NewcastleAustralia

1/07/2011 -

Professor

University of NewcastleImmunology & MicrobiologyAustralia

1/07/2007 - 1/06/2011

Associate Professor

University of NewcastleImmunology & MicrobiologyAustralia

1/01/2007 -

Head of Discipline of Immunology & Microbiology

University of NewcastleAustralia

1/01/2005 - 31/12/2007

Organiser and Convenor - Newcastle Asthma Meeting

University of NewcastleAustralia

1/01/2005 - 1/06/2007

Senior Lecturer

University of NewcastleImmunology & MicrobiologyAustralia

1/10/1999 -

Group leader Microbiology Research Group

University of NewcastleAustralia

1/10/1999 - 1/12/2004

Lecturer in Microbiology

University of NewcastleAustralia

1/10/1999 - 1/12/2004

Lecturer

University of NewcastleImmunology & MicrobiologyAustralia

Membership

Dates

Title

Organisation / Department

Membership - School of Biomedical Sciences Executive

University of NewcastleAustralia

Member - Organising Committee of the International Symposium on Pneumococci and Pneumococcal Diseases

Organising Committee of the International Symposium on Pneumococci and Pneumococcal DiseasesAustralia

Invited Academic Member - Nuways Committee for Streamlining Research Processes

Pregnancy provides a unique challenge for maternal immunity, requiring the ability to tolerate the presence of a semi-allogeneic foetus, and yet still being capable of inducing an... [more]

Pregnancy provides a unique challenge for maternal immunity, requiring the ability to tolerate the presence of a semi-allogeneic foetus, and yet still being capable of inducing an immune response against invading pathogens. To achieve this, numerous changes must occur in the activity and function of maternal immune cells throughout the course of pregnancy. Respiratory viruses take advantage of these changes, altering the sensitive balance of maternal immunity, leaving the mother with increased susceptibility to viral infections and increased disease severity. Influenza virus is one of the most common respiratory virus infections during pregnancy, leading to an increased risk of ICU hospitalisations, pneumonia, acute respiratory distress syndrome and even death. Whilst much research has been performed to understand the changes that must take place in maternal immunity during pregnancy, considerable work is still needed to fully comprehend this tremendous feat. To date, few studies have focused on the alterations that occur in maternal immunity during respiratory virus infections. This review highlights the role of dendritic cells (DCs) and CD8 T cells during pregnancy, and the changes that occur in these antiviral cells following influenza virus infections.

The immune and nociceptive systems are shaped during the neonatal period where they undergo fine-tuning and maturation. Painful experiences during this sensitive period of develop... [more]

The immune and nociceptive systems are shaped during the neonatal period where they undergo fine-tuning and maturation. Painful experiences during this sensitive period of development are known to produce long-lasting effects on the immune and nociceptive responses. It is less clear, however, whether inflammatory pain responses are primed by neonatal exposure to mild immunological stimuli, such as with lipopolysaccharide (LPS). Here, we examine the impact of neonatal LPS exposure on inflammatory pain responses, peripheral and hippocampal interleukin-1Ã (IL-1Ã), as well as mast cell number and degranulation in preadolescent and adult rats. Wistar rats were injected with LPS (0.05 mg/kg IP, Salmonella enteritidis) or saline on postnatal days (PNDs) 3 and 5 and later subjected to the formalin test at PNDs 22 and 80-97. At both time-points, and one-hour after formalin injection, blood and hippocampus were collected for measuring circulating and central IL-1Ã levels using ELISA and Western blot, respectively. Paw tissue was also isolated to assess mast cell number and degree of degranulation using Toluidine Blue staining. Behavioural analyses indicate that at PND 22, LPS-challenged rats displayed enhanced flinching (p

Exposure to particulate matter (PM), a major component of air pollution, contributes to increased morbidity and mortality worldwide. Inhaled PM induces innate immune responses by airway epithelial cells that may lead to the exacerbation or de novo development of airway disease. We have previously shown that 10-mm PM (PM10) activates the nucleotide-binding domain, leucine-rich repeat protein (NLRP) 3 inflammasome in human airway epithelial cells. Our objective was to determine the innate and adaptive immune responses mediated by the airway epithelium NLRP3 inflammasome in response to PM10 exposure. Using in vitro cultures of human airway epithelial cells and in vivo studies with wild-type and Nlrp3-/- mice, we investigated the downstream consequences of PM10-induced NLPR3 inflammasome activation on cytokine production, cellular inflammation, dendritic cell activation, and PM10-facilitated allergic sensitization. PM10 activates an NLRP3 inflammasome/IL-1 receptor I (IL-1RI) axis in airway epithelial cells, resulting in IL-1b, CC chemokine ligand-20, and granulocyte/macrophage colony-stimulating factor production, which is associated with dendritic cell activation and lung neutrophilia. Despite these profound innate immune responses in the airway epithelium, the NLRP3 inflammasome/IL-1RI axis is dispensable for PM10-facilitated allergic sensitization. We demonstrate the importance of the lung NLRP3 inflammasome in mediating PM10 exposure-associated innate, but not adaptive, immune responses. Our study highlights a mechanism by which PM10 exposure can contribute to the exacerbation of airway disease, but not PM10-facilitated allergic sensitization.

Wild aquatic birds are recognized as the natural reservoir of avian influenza A viruses (AIV), but across high and low pathogenic AIV strains, scientists have yet to rigorously id... [more]

Wild aquatic birds are recognized as the natural reservoir of avian influenza A viruses (AIV), but across high and low pathogenic AIV strains, scientists have yet to rigorously identify most competent hosts for the various subtypes. We examined 11,870 GenBank records to provide a baseline inventory and insight into patterns of global AIV subtype diversity and richness. Further, we conducted an extensive literature review and communicated directly with scientists to accumulate data from 50 non-overlapping studies and over 250,000 birds to assess the status of historic sampling effort. We then built virus subtype sample-based accumulation curves to better estimate sample size targets that capture a specific percentage of virus subtype richness at seven sampling locations. Our study identifies a sampling methodology that will detect an estimated 75% of circulating virus subtypes from a targeted bird population and outlines future surveillance and research priorities that are needed to explore the influence of host and virus biodiversity on emergence and transmission.

The dynamic interplay between regulatory T cells (Tregs) and effector T cells (Teffs) governs the balance between tolerance and effector immune responses. Perturbations of Treg frequency and function or imbalances in Treg/Teff levels are associated with the development of autoimmunity. The factors that mediate these changes remain poorly understood and were investigated in this study in murine autoimmune arthritis. Tregs displayed a stable phenotype in arthritic mice and were fully functional in in vitro suppression assays. However, their expansion was delayed relative to Teffs (T follicular helper cells and Th17 cells) during the early stages of autoimmune reactivity. This imbalance is likely to have led to insufficient Treg control of Teffs and induced autoimmunity. Moreover, a counterregulatory and probably IL-7-driven increase in thymic Treg production and recruitment to inflamed tissues was too slow for disease prevention. Increased Teff over Treg expansion was further aggravated by inflammation and lymphopenia. Both these conditions contribute to autoimmune pathogenesis and were accompanied by decreases in the availability of IL-2 and increases in levels of IL-21. IL-2 neutralization or supplementation was used to show that Treg expansion mainly depended on this cytokine. IL-21R2/2 cells were used to demonstrate that IL-21 promoted the maintenance of Teffs. Thus, at inflammatory sites in experimental arthritis, a deficit in IL-2 hampers Treg proliferation, whereas exaggerated IL-21 levels overwhelm Treg control by supporting Teff expansion. This identifies IL-2 and IL-21 as targets for manipulation in therapies for autoimmunity.

Introduction: Neutrophil extracellular traps (NETs) have not been demonstrated after trauma and subsequent surgery. Neutrophil extracellular traps are formed from pure mitochondri... [more]

Introduction: Neutrophil extracellular traps (NETs) have not been demonstrated after trauma and subsequent surgery. Neutrophil extracellular traps are formed from pure mitochondrial DNA (mtDNA) under certain conditions, which is potently proinflammatory. We hypothesized that injury and orthopedic trauma surgery would induce NET production with mtDNA as a structural component. Methods: Neutrophils were isolated 8 trauma patients requiring orthopedic surgery postinjury and up to 5 days postoperatively. Four healthy volunteers provided positive and negative controls. Total hip replacement patients acted as an uninjured surgical control group. Neutrophil extracellular traps were visualized with DNA (Hoechst 33342TM/Sytox Green/MitoSox/MitoTracker) stains using live cell fluorescence microscopy with downstream quantitative polymerase chain reaction analysis of DNA composition. Results: Neutrophil extracellular traps were present after injury in all 8 trauma patients. They persisted for 5 days postoperatively. Delayed surgery resulted in NET resolution, but they reformed postoperatively. Total hip replacement patients developed NETs postoperatively, which resolved by day 5. Quantitative polymerase chain reaction analysis of NET-DNA composition revealed that NETs formed after injury and surgery were made of mtDNA with no detectable nuclear DNA component. Conclusions: Neutrophil extracellular traps formed after major trauma and subsequent surgery contain mtDNA and represent a novel marker of heightened innate immune activation. They could be considered when timing surgery after trauma to prevent systemic NET-induced inflammatory complications.

The pathogenesis of chronic obstructive pulmonary disease (COPD) and its exacerbations, are intricately linked to colonisation and infection with bacteria and other microbes. Desp... [more]

The pathogenesis of chronic obstructive pulmonary disease (COPD) and its exacerbations, are intricately linked to colonisation and infection with bacteria and other microbes. Despite their undeniable importance, we have a poor understanding of the complex relationships between COPD phenotypes, physiology, cellular and molecular biology and the roles of colonising microbe or infecting pathogens. The management algorithms for the care of patients with COPD that include microbial influences, have almost exclusively been developed using microbial methods that were entirely dependent on the ability to grow bacteria on suitable media. The shortcomings of this approach are becoming clear now that it is possible to completely and accurately define the microbial ecology of ecosystems using genomic methods, which do not rely on the ability to cultivate the organisms present. Whilst our appreciation of the relationships between some bacterial ecosystems and the organ in which they reside in humans is now relatively advanced, this is not true for lung. This perspective serves to highlight the growing importance of including an accurate description of bacterial ecology in any attempt to decipher the pathobiology of COPD. While this field is in its infancy, there is significant potential to gain new insights which will translate into more rational and effective treatment algorithms for patients with COPD.

Hansbro PM, Starkey MR, Mattes J, Horvat JC, 'Pulmonary immunity during respiratory infections in early life and the development of severe asthma', Annals of the American Thoracic Society, 11 S297-S302 (2014) [C1]

Asthma affects 10% of the population in Westernized countries, being most common in children. It is a heterogeneous condition characterized by chronic allergic airway inflammation... [more]

Asthma affects 10% of the population in Westernized countries, being most common in children. It is a heterogeneous condition characterized by chronic allergic airway inflammation, mucus hypersecretion, and airway hyperresponsiveness (AHR) to normally innocuous antigens. Combination therapies with inhaled corticosteroids and bronchodilators effectively manage mild to moderate asthma, but there are no cures, and patients with severe asthma do not respond to these treatments. The inception of asthma is linked to respiratory viral (respiratory syncytial virus, rhinovirus) and bacterial (Chlamydia, Mycoplasma) infections. The examination of mouse models of early-life infections and allergic airway disease (AAD) provides valuable insights into the mechanisms of disease inception that may lead to the development of more effective therapeutics. For example, early-life, but not adult, Chlamydia respiratory infections in mice permanently modify immunity and lung physiology. This increases the severity of AAD by promoting IL-13 expression, mucus hypersecretion, and AHR. We have identified novel roles for tumor necrosis factor-related apoptosisinducing ligand (TRAIL) and IL-13 in promoting infection-induced pathology in early life and subsequent chronic lung disease. Genetic deletion of TRAIL or IL-13 variously protected against neonatal infection-induced inflammation, mucus hypersecretion, altered lung structure, AHR, and impaired lung function. Therapeutic neutralization of these factors prevented infection-induced severe AAD. Other novel mechanisms and avenues for intervention are also being explored. Such studies indicate the immunological mechanisms that may underpin the association between early-life respiratory infections and the development of more severe asthma and may facilitate the development of tailored preventions and treatments.

News

Professor Phil Hansbro has been awarded more than $443,000 in ARC Discovery Project funding commencing in 2015 for his research project Elucidating the post-transcriptional regulation of mast cell proteases.

Sinister specks of a molecule known as ASC are escaping from cells then coursing through the body to exacerbate the biological inflammatory response in major airway diseases such as asthma and emphysema.

Respiratory researcher Professor Phil Hansbro won the prestigious 2013 Award for Research Excellence tonight as more than $1.4 million in grant funding was awarded and acknowledged in the Hunter Medical Research Institute's 2013 Awards Night.

Newcastle researchers have contributed to the discovery of a protein in the
female reproductive tract that protects against sexually transmitted diseases
(STDs) such as chlamydia and herpes simplex virus (HSV).

Professor Phil Hansbro

Position

Professor, NHMRC Fellow and Brawn FellowSchool of Biomedical Sciences and PharmacyFaculty of Health and Medicine